In 1999, Nagata et al identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), a novel G protein-coupled receptor (GPCR) belonging to the leucocyte chemoattractant receptor family.
The CRTH2 receptor is selectively expressed from a wide variety of tissues including the brain, lung and lymphoid organs in mouse (Abe et al., Gene (1999) 227 (1):71–7). With respect to expression from immune system cells, it is reported that CRTH2 receptor is selectively expressed on Th2 cells, eosinophils and basophils, but not Th1 cells, B cells and NK cells in human (Nagata et al., FEBS Letters (1999) 459 (2):195–9).
Bauer et al, (see EP1170594A2) identified Prostaglandine D2 (PGD2) as the endogenous ligand of CRTH2. PGD2 is released from immunologically stimulated mast cells and Th2 cells.
Interaction of CRTH2 with PGD2 plays a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. In addition, CRTH2 mediates PGD2 dependent cell migration of blood eosinophils and basophils.
Allergic asthma and allergic rhinitis are diseases that currently affect about 10% of the population, and that number appears to be increasing (Bush, R. K. a. G., John W., Handbook of asthma and rhinitis. 1st ed. (1997), Abingdon: Blackwell Science. 270). Currently numerous classes of pharmaceutical agents are widely used to treat these diseases, for example, antihistamines, decongestants, β2 agonists, anticholinergics, methylxanthines, cromolyns, corticosteroids, and leukotriene modulators. Generally however, the usefulness of these agents is limited by side effects and low efficacy. Accordingly, there is a critical medical need to identify pharmaceutically active compounds that interfere with key steps of the inflammatory and immunological processes that contribute to these disease states, and other inflammatory conditions.
EP 987251 discloses cholesteryl ester transfer protein of formula
for use in the treatment of diseases affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides such as atherosclerosis and cardiovascular diseases.
WO91/05549 discloses compounds of formula
for use as vasodilator, hypotensive agent, water diuretics and platelet agglutination inhibitor.
U.S. Pat. No. 4,521,607 discloses compounds of formula
for use as antihypertensives.
WO 02/079165 discloses compounds of formula
as STAT6 signaling pathway modulators.